The overall goal of this proposal is to determine the role of the plasma phospholipid transfer protein (PLTP) in lipoprotein metabolism and atherosclerosis. In vitro studies have provided evidence that PLTP plays a central role in the maintenance of cholesterol homeostasis, the distribution of lipids among lipoproteins, and is likely to be particularly important in the regulation of HDL levels and composition. Mice models will be developed that either over express or lack PLTP and these mice will be cross bred with atherosclerosis susceptible models in order to determine how PLTP expression in the mouse influences lipoprotein metabolism and atherosclerosis. Lipids, lipoproteins, and atherosclerotic lesions will be evaluated in these mice on either a chow diet or a high fat high cholesterol diet. The effect of cholesterol loading and inhibition of cellular proliferation on expression and secretion of PLTP by cultured cells will be examined and it will be determined if and by what mechanisms PLTP promotes lipid transport from cells. A better understanding of the physiological role of PLTP may permit new therapeutic approaches to lipoprotein disorders associated with premature coronary disease.